The present invention relates to compounds having pharmaceutical properties, and in particular, to compounds useful for preventing and treating inflammatory bowel diseases. More specifically, the present invention relates to a method for treating patients suffering from an idiopathic chronic inflammatory bowel disease (e.g., ulcerative colitis), and in particular, to compositions of matter useful as pharmaceutical compositions in the prevention and treatment of such a disease.
Idiopathic ulcerative colitis (UC) is a recurrent acute and chronic ulcero-inflammatory disorder principally affecting the rectum and left colon, but sometimes the entire large bowel. See, Kirsner et al., N. Engl. J. Med., Vol. 306, pp.775-837 (1982). UC encompasses a spectrum of diffuse, continuous, superficial inflammation of the colon, which begins in the rectum and extends to a variable proximal level. See, Cecil Textbook Of Medicine, 19th Edition, p. 699, Ed. by Wyngaarden et al. (1992). Matters relating to the etiology (i.e., definitive etiopathogenesis is not kayown), epidemiology, pathogenesis, pathology, symptoms, diagnosis (e.g., endoscopy and radiography), and complications (e.g., cancer, intestinal complications such as rectal bleeding and toxic megacolon, and extraintestinal complications such as anemia and leukocytosis) are set forth in relatively complete detail in Cecil Textbook of Medicine (supra).
The manner in which UC is treated can vary, and typically the medical treatment depends upon the severity of the symptoms exhibited by the patient. Corticosteroids (e.g., prednisone), antibiotics (e.g., tetracycline, sulfa-trimethoprim, metronidazole and cephalexin) and inununosuppressivcs (e.g., 6-mercaptopurine and azathioprine) often are used for treating UC. Anti-inflammatory agents (e.g., sulfasalazine and mesalamine) are effective to some degree in some patients for the treatment of acute UC. Certain anti-inflammatory agents are available commercially as Asacol from Rolm Pharma G.m.b.H., Dipentum from Kabi Pharmacia AB and Rowasa from Solvay Pharmaceuticals. In more severe cases or when the anti-inflammatory agents fail to relieve the symptoms of UC, surgical procedures are used. Typical surgical procedures include colectomy, proctocolectomy and ileostomy. See, Cecil Textbook of Medicine (supra). Other treatment methods for gastrointestinal disorders have been proposed in U.S. Pat. Nos. 5,312,818 to Rubin et al, 5,324,738 to Dinan et al., 5,331,013 to Ahlman et al. and 5,340,801 to Ewing et al.
Epidemiology studies indicate a possibility that lifestyle may play a role in the development of UC. See, Shievananda et al., Current opinion in Gastroenterology, Vol. 9, pp.560-565 (1993). Factors such as the environment and cigarette smoking have been examined for associations with UC. See, Lashnet, Digestive Diseases and Sciences, Vol. 35 (7), pp. 827-832 (1992) and Calkins, Digestive Diseases and Sciences, Vol. 34 (12), pp. 1841-1854 (1989). Several clinical studies have reported that cigarette smoking improves the course of UC. See, Rudra et al., Scand. J. Gastroenterol, Vol. 24 (Suppl 170), pp. 61-63 (1989); and Thomas and Rhodes, International Symposium on Nicotine, S38, 1994, eds. Clarke et al. Several hypotheses have been proposed to explain the inverse relationship between cigarette smoking and UC. These hypotheses include smoking-associated changes in colonic mucus (Amaral-Corfield et al., Med. Sci. Res., Vol. 19, pp. 309-310 (1991 )); intestinal permeability (Prytz et al., Scand. J. Gastroenterol, Vol. 24, pp. 1084-1088 (1989)); rectal blood flow (Srivastava et al., Gut, Vol. 31, pp. 1021-1024 (1990)); immunoglobulin secretion (Barton et al., Gut, Vol. 31, pp. 378-382 (1990); Srivastava et al., Eur. J. Gastroenterol. & Hepatol., Vol. 3, pp. 815-818 ( 1991)); and antioxidant defenses (Cope et al., Gut, Vol. 33, pp.721-723 (1992)). Nicotine has been tested as a treatment for active UC. See, Srivastava et al., Eur. J. Gastroenterol. & Hepatol., Vol. 3, pp. 815 -818 ( 1991 )). Improvement of UC symptoms was also observed following the use of nicotine gum (Lashner et al., Digestive Diseases and Sciences, Vol. 35(7), pp. 827-832 (1990)) and nicotine patch (Pullan et al., N. Engl. J. Med., Vol. 330, pp. 811-815 (1994)).
It would be desirable to provide a pharmaceutical composition useful for the prevention and treatment of inflammatory bowel diseases. It would be highly beneficial to provide individuals suffering from certain inflammatory bowel diseases with interruption of the symptoms of those diseases by the administration of a compound which has nicotinic pharmacology and which has a beneficial effect upon the functioning of the gastrointestinal tract, but which does not provide any significant associated side effects (e.g., increased heart rate and blood pressure) attendant with interaction of that compound with cardiovascular sites. It would be highly desirable to provide a pharmaceutical composition incorporating a compound which interacts with nicotinic receptors which have the potential to affect the functioning of the gastrointestinal tract, but which does not significantly affect those receptors which have the potential to induce side effects (e.g., appreciable pressor cardiovascular effects and appreciable activity at skeletal muscle sites).